The hypothalamus integrates diverse sensory and metabolic cues and coordinates specific behavioral, autonomic, and endocrine responses that maintain homeostasis. Often these responses are modulated by neuropeptide systems. The orexins, or hypocretins, comprise a family of neuropeptides that are synthesized solely in the brain by diffusely projecting neurons in the lateral hypothalamic area. Much attention has been given to the roles of orexin and the two orexin receptors in feeding behavior and the control of sleep/wake state. Orexins have also been implicated in the control of neuroendocrine function and maintaining autonomic homeostasis, although little is known about the role of orexin in regulating central autonomic pathways. In the experiments outlined in this proposal, we offer a functional neuroanatomical model by which orexin might modulate the sympathetic nervous system and test this model using neuroanatomical techniques, brain microinjections, and genetic knockout mice. Using blood pressure telemetry measurement in unanesthetized and unrestrained animals, as well as others indicators of sympathetic outflow, we hope to be able to determine the role orexin plays in maintaining autonomic homeostasis.